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Yun Xing,1,2 Xiao-Zhen Feng,2 Lipeng Zhang,1 Jiating Hou,2 Guo-Cheng Han,2 Zhencheng Chen2 1Henan Province of Key Laboratory of New Optoelectronic Functional Materials, College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang, 2School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, Guangxi, People’s Republic of China Abstract: Soluble beta-amyloid (Aβ) oligomer is believed to be the most important toxic species in the brain of Alzheimer’s disease (AD) patients. Thus, it is critical to develop a simple method for the selective detection of Aβ oligomer with low cost and high sensitivity. In this paper, we report an electrochemical method for the detection of Aβ oligomer with a peptide as the bioreceptor and silver nanoparticle (AgNP) aggregates as the redox reporters. This strategy is based on the conversion of AgNP-based colorimetric assay into electrochemical analysis. Specifically, the peptide immobilized on the electrode surface and presented in solution triggered together the in situ formation of AgNP aggregates, which produced a well-defined electrochemical signal. However, the specific binding of Aβ oligomer to the immobilized peptide prevented the in situ assembly of AgNPs. As a result, a poor electrochemical signal was observed. The detection limit of the method was found to be 6 pM. Furthermore, the amenability of this method for the analysis of Aβ oligomer in serum and artificial cerebrospinal fluid (aCSF) samples was demonstrated. Keywords: electrochemical biosensors, Alzheimer’s disease, beta-amyloid oligomer, peptide, silver nanoparticles

Gallbladder cancer (GBC) is a common malignant cancer in the biliary system, which poses a serious threat to human health. It is urgent to explore ideal drugs for the treatment of GBC. Matrine is the main active ingredient of Sophora flavescentis, with a wide range of biological activities encompassing anti-inflammatory, antiviral, immunomodulatory, and anti-tumor. However, the underlying mechanism by which Matrine treats GBC is still unclear. The purpose of this study is to investigate the anti-tumor effects of Matrine on GBC in vivo and in vitro and to clarify the potential regulatory mechanisms. Here, we found that Matrine had a significant killing effect on GBC through CCK8 and flow cytometry, including arrest of cell cycle, inhibition of GBC cell, and induction of apoptosis. Further in vivo studies confirmed the inhibitory effect of Matrine on tumor growth in NOZ xenografted nude mouse. At the same time, Matrine also significantly suppressed the migration and invasion of GBC cells through scratch and Transwell experiments. In addition, by detecting the mRNA and protein levels of epithelial-mesenchymal transition (EMT) and matrix metalloproteinases, Matrine furtherly substantiated the inhibitory role on invasion and migration of GBC. From a mechanistic perspective, network pharmacology analysis suggests that the potential targets of Matrine in the treatment of GBC are enriched in the PI3K/AKT signaling pathway. Subsequently, Matrine effectively decreased the abundance of p-PI3K and p-AKT protein in vivo and in vitro. More importantly, PI3K activator (740 Y-P) antagonized the anti-tumor effect of Matrine, while PI3K inhibitor (LY294002) increased the sensitivity of Matrine for GBC. Based on the above findings, we conclude that Matrine inhibits the invasion and migration of GBC by regulating PI3K/AKT signaling pathway. Our results indicate the crucial role and regulatory mechanism of Matrine in suppressing the growth of GBC, which provides a theoretical basis for Matrine to be a candidate drug for the treatment and research of GBC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Facial nerve schwannomas (FNSs) are rare intracranial tumors, and the optimal management of these tumors remains unclear. We investigated the long-term follow-up results of FNS with good facial nerve function., Methods: At nine medical centers in the Korean Facial Nerve Study Group, 43 patients undergoing observation periods longer than 12 months for FNS with good facial nerve function (House-Brackmann grade ≤ II) were enrolled, and clinical and radiographic data were obtained for these cases., Results: The mean follow-up period was 63 months. In the majority of cases, tumors involved multiple segments (81.4%) and only eight cases were confined to a single site. There were no cases where the tumor was confined to the extratemporal region. Tumor size increased slightly, with an average estimated change of 0.48 mm/year. Twenty (46.5%) of 43 patients showed no change in tumor size. Seven patients (16.3%) showed worsening House-Brackmann (H-B) grade, of which two patients deteriorated from H-B grade I to II, four worsened to grade III, and one deteriorated to grade IV. The remaining 36 patients (83.7%) showed no change in facial nerve function. There was no difference in H-B grade according to tumor size at the time of diagnosis or change in tumor size., Conclusion: We conducted a large-scale observational study of FNS with good facial nerve function. Our study showed that many patients maintained facial nerve function during long-term follow-up. Conservative management with regular examination and imaging can be an appropriate option for managing FNS with good facial nerve function., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

KCNQ4 is a voltage-gated K + channel was reported to distribute over the basolateral surface of type 1 vestibular hair cell and/or inner surface of calyx and heminode of the vestibular nerve connected to the type 1 vestibular hair cells of the inner ear. However, the precise localization of KCNQ4 is still controversial and little is known about the vestibular phenotypes caused by KCNQ4 dysfunction or the specific role of KCNQ4 in the vestibular organs. To investigate the role of KCNQ4 in the vestibular organ, 6-g hypergravity stimulation for 24 h, which represents excessive mechanical stimulation of the sensory epithelium, was applied to p.W277S Kcnq4 transgenic mice. KCNQ4 was detected on the inner surface of calyx of the vestibular afferent in transmission electron microscope images with immunogold labelling. Vestibular function decrease was more severe in the Kcnq4 p.W277S/p.W277S mice than in the Kcnq4 +/+ and Kcnq4 +/p.W277S mice after the stimulation. The vestibular function loss was resulted from the loss of type 1 vestibular hair cells, which was possibly caused by increased depolarization duration. Retigabine, a KCNQ activator, prevented hypergravity-induced vestibular dysfunction and hair cell loss. Patients with KCNQ4 mutations also showed abnormal clinical vestibular function tests. These findings suggest that KCNQ4 plays an essential role in calyx and afferent of type 1 vestibular hair cell preserving vestibular function against excessive mechanical stimulation., (© 2024. The Author(s).)

Background: Gallbladder cancer (GBC) poses a significant risk to human health. Its development is influenced by numerous factors, particularly the homeostasis of reactive oxygen species (ROS) within cells. This homeostasis is crucial for tumor cell survival, and abnormal regulation of ROS is associated with the occurrence and progression of many cancers. Dihydrotanshinone I (DHT I), a biologically effective ingredient isolated from Salvia miltiorrhiza, has exhibited cytotoxic properties against various tumor cells by inducing apoptosis. However, the precise molecular mechanisms by which dht I exerts its cytotoxic effects remain unclear., Purpose: To explore the anti-tumor impact of dht I on GBC and elucidate the potential molecular mechanisms., Methods: The proliferation of GBC cells, NOZ and SGC-996, was assessed using various assays, including CCK-8 assay, colony formation assay and EdU staining. We also examined cell apoptosis, cell cycle progression, ROS levels, and alterations in mitochondrial membrane potential to delve into the intricate molecular mechanism. Quantitative PCR (qPCR), immunofluorescence staining, and Western blotting were performed to evaluate target gene expression at both the mRNA and protein levels. The correlation between nuclear factor erythroid 2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap1) were examined using co-immunoprecipitation. Finally, the in vivo effect of dht I was investigated using a xenograft model of gallbladder cancer in mice., Results: Our research findings indicated that dht I exerted cytotoxic effects on GBC cells, including inhibiting proliferation, disrupting mitochondrial membrane potential, inducing oxidative stress and apoptosis. Our in vivo studies substantiated the inhibition of dht I on tumor growth in xenograft nude mice. Mechanistically, dht I primarily targeted Nrf2 by promoting Keap1 mediated Nrf2 degradation and inhibiting protein kinase C (PKC) induced Nrf2 phosphorylation. This leads to the suppression of Nrf2 nuclear translocation and reduction of its target gene expression. Moreover, Nrf2 overexpression effectively counteracted the anti-tumor effects of dht I, while Nrf2 knockdown significantly enhanced the inhibitory effect of dht I on GBC. Meanwhile, PKC inhibitors and nuclear import inhibitors increased the sensitivity of GBC cells to dht I treatment. Conversely, Nrf2 activators, proteasome inhibitors, antioxidants and PKC activators all antagonized dht I induced apoptosis and ROS generation in NOZ and SGC-996 cells., Conclusion: Our findings indicated that dht I inhibited the growth of GBC cells by regulating the Keap1-Nrf2 signaling pathway and Nrf2 phosphorylation. These insights provide a strong rationale for further investigation of dht I as a potential therapeutic agent for GBC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Human chorionic gonadotropin (HCG), a vital protein for pregnancy determination and a marker for trophoblastic diseases, finds application in monitoring early pregnancy and ectopic pregnancy. This study presents an innovative approach employing electrochemical immunosensors for enhanced HCG detection, utilizing Anti-HCG antibodies and gold nanoparticles (AuNPs) in the sensor platform. Two sensor configurations were optimized: BSA/Anti-HCG/c-AuNPs/MEL/e-AuNPs/SPCE with [Fe(CN) 6 ] 3-/4- as a redox probe (1) and BSA/Anti-HCG/PPy/e-AuNPs/SPCE using polypyrrole (PPy) as a redox probe (2). The first sensor offers linear correlation in the 0.10-500.00 pg∙mL -1 HCG range, with a limit of detection (LOD) of 0.06 pg∙mL -1 , sensitivity of 32.25 μA∙pg -1 ∙mL∙cm -2 , RSD <2.47 %, and a recovery rate of 101.03-104.81 %. The second sensor widens the HCG detection range (40.00 fg∙mL -1 -5.00 pg∙mL -1 ) with a LOD of 16.53 fg∙mL -1 , ensuring precision (RSD <1.04 %) and a recovery range of 94.61-106.07 % in serum samples. These electrochemical immunosensors have transformative potential in biomarker detection, offering enhanced sensitivity, selectivity, and stability for advanced healthcare diagnostics., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we propose a deep learning-based nystagmus detection algorithm using video oculography (VOG) data to diagnose benign paroxysmal positional vertigo (BPPV). Various deep learning architectures were utilized to develop and evaluate nystagmus detection models. Among the four deep learning architectures used in this study, the CNN1D model proposed as a nystagmus detection model demonstrated the best performance, exhibiting a sensitivity of 94.06 ± 0.78%, specificity of 86.39 ± 1.31%, precision of 91.34 ± 0.84%, accuracy of 91.02 ± 0.66%, and an F 1 -score of 92.68 ± 0.55%. These results indicate the high accuracy and generalizability of the proposed nystagmus diagnosis algorithm. In conclusion, this study validates the practicality of deep learning in diagnosing BPPV and offers avenues for numerous potential applications of deep learning in the medical diagnostic sector. The findings of this research underscore its importance in enhancing diagnostic accuracy and efficiency in healthcare.

Alpha-fetoprotein (AFP) is a glycoprotein that has many important physiological functions, including transportation, immunosuppression, and induction of apoptosis by T lymphocytes. AFP is closely related to the development of hepatocellular carcinoma and many kinds of tumors, all of which can show high concentrations, so it is used as a positive test indicator for many kinds of tumors. This paper reviews recent advances in the detection of the tumor marker AFP based on three immuno-biosensors: electrochemical (EC), photoelectrochemical (PEC), and electrochemical luminescence (ECL). The electrodes are modified by different materials or homemade composites, different signaling molecules are selected as single probes or dual probes for the detection of AFP. The detection limit was as low as 3 fg/mL, which indicated that the AFP immunosensor had achieved highly sensitive detection. In addition, we also reviewed and summarized the current development status and application prospect of AFP immunoelectrochemical sensors. There are not too many researches on immunosensors based on dual-signal ratios, and the commonly used probes are methylene blue (MB) and ferrocene (Fc). It would be more innovative to have more novel signaling molecules as probes to prepare dual-signal ratio sensors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A visual detection method for malachite green (MG) in food was established based on 'double-response-OFF' ratiometric fluorescent paper-based sensor. Biomass carbon quantum dots (BCQDs) using broad bean shell, and Ti 3 C 2 MXene quantum (MQDs) dots modified by ethylenediamine were synthesized by solvothermal method. The MG and two kinds of quantum dots could undergo static quenching, and the fluorescence color of two kinds of quantum dots gradually changed from red to blue, eventually the fluorescence was quenched, and the pattern had a two-stage linear relationship using fluorescent spectrofluorometer in the range of 0.1-140.0 μ M and the detection limit of 0.07 μ M. On this basis, a BCQDs/MQDs ratiometric fluorescence paper-based sensor was constructed and applied to fish sample. Through mobile phone software-Color recognizer, RGB values of fluorescent paper-based sensor at various concentrations of MG were extracted. The results showed that MG concentration was linearly correlated with R ' value of RGB in the range of 20.0-140.0 μ M with 16.5 μ M detection limit. The method had been applied to the determination of canned fish and fresh basa fish samples, and the recovery rates were 97.33%-108.93% and 96.04%-117.97%, respectively. It proved that the ratiometric fluorescent paper-based sensor could be used for the rapid visual quantitative detecting MG in real samples., (© 2024 IOP Publishing Ltd.)

High-sensitivity C-reactive protein (hs-CRP) is an inflammatory biomarker and can accurately predict the development of cardiovascular disease (CVD). We synthesized a core-shell structure PPy-Au nanocomposite in situ by chemically oxidizing pyrrole (Py) with HAuCl 4 and the produced Au nanoparticles realized the doping in the polymerization. Analysis of morphology and energy spectrum as well as electrochemical characterization confirmed the successful one-pot synthesis. The conductive polymers with porous structure provide abundant sites for anti-CRP binding and effectively enhanced the sensitivity of the label-free BSA/anti-CRP/PPy-Au/GCE immunosensor. Its analytical performance was observed using differential pulse voltammetry (DPV), with a linear range from 0.0005 to 60 μg mL -1 and a detection limit of 0.17 ng mL -1 . The platform demonstrated satisfactory selectivity, stability, and reproducibility. To validate its clinical application, we detected CRP in human serum samples with a recovery rate of 101.00-105.95% and investigated the consistency of the developed method and immunoturbidimetry with a deviation between -1.2% and +3.2%, suggesting great potential for use in point-of-care testing (POCT)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We report the fabrication of a facile sensor using heme conjugated with gold nanoparticles (AuNPs) in situ on a glass carbon electrode (GCE) for the ultrasensitive determination of biotin without antibody or streptavidin. The use of heme and AuNPs as dual amplifiers allows a very broad detection range from 0.0050 to 50.0000 μmol·L -1 and a very low detection limit of 0.0016 μmol·L -1 . The mechanistic aspects were elucidated using electrochemical analyses and frontier orbital calculations showing that the electrooxidation of biotin involves a one-electron and a one-proton transfer, generating biotin sulfoxide. The heme/AuNPs/GCE sensor exhibited excellent selectivity, reproducibility and stability, indicating high robustness. The recovery was between 97.20 and 105.70% with RSD less than 8.71%, suggesting good practicability. Our studies demonstrate that this approach can be used to detect and quantify biotin in a range of foods, including milk, infant formula, flour, orange juice, mango juice, egg white and egg yolk. Furthermore, all measurements do not require any intricate preparation or pre-treatment of the foods, thus representing a great potential for point-of-care testing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Orbital apex syndrome (OAS) is a rare condition that usually occurs due to damage to surrounding inner and surrounding bone tissue. Orbital apex syndrome may result from a variety of conditions that cause damage to the superior orbital fissure and to the optic canal leading to optic nerve (II) dysfunction. We recently experienced a rare case of sphenoidal Aspergillosis , which damaged the adjacent cavernous sinus structures and led to the definite symptom of bilateral OAS in a 77-year-old male. We present this rare case with a brief review of these disease's entities., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

C-reactive protein (CRP) is a protein biomarker for acute phase response. Herein, we fabricate a highly sensitive electrochemical immunosensor for CRP on a screen-printed carbon electrode (SPCE) with indole as a novel electrochemical probe and Au nanoparticles for signal amplification. Amongst, indole appeared as transparent nanofilms on the electrode surface, and underwent a one-electron and one-proton transfer to form oxindole during the oxidation process. Upon optimization of experimental conditions, a logarithmic correlation between CRP concentration (0.0001-100 μg∙mL -1 ) and response current was revealed with a detection limit of 0.03 ng∙mL -1 and a sensitivity of 5.7055 μA∙μg -1 ∙mL∙cm -2 . The sensor exhibited exceptionally distinction selectivity, reproducibility and stability of the electrochemical immunosensor studied. The recovery rate of CRP in human serum samples determined by the standard addition method, ranged between 98.2-102.2%. Overall, the developed immunosensor is promising, and has the potential for CRP detection in real human serum samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: The impacts of ventilation tube (VT) type and effusion composition on the VT extrusion rate and complications in children with otitis media remain unclear. This part II study evaluated the factors affecting the extrusion rate, recurrence rate, and complications of VT insertion., Methods: A prospective study was conducted between June 2014 and December 2016 (the EVENT study [analysis of the effectiveness of ventilation tube insertion in pediatric patients with chronic otitis media]), with follow-up data collected until the end of 2017. Patients aged <15 years diagnosed with otitis media with effusion who received VT insertion were recruited at 15 tertiary hospitals. The primary outcomes were time to extrusion of VT, time to effusion recurrence, and complications., Results: Data from 401 patients were analyzed. After excluding the., Results: of long-lasting tubes (Paparella type II and T-tubes), silicone tubes (Paparella type I) exhibited a significantly longer extended time to extrusion (mean, 400 days) than titanium tubes (collar-button-type 1.0 mm: mean, 312 days; P<0.001). VT material (hazard ratio [HR], 2.117, 95% confidence interval [CI], 1.254-3.572; P=0.005), age (HR, 3.949; 95% CI, 1.239-12.590; P=0.02), and effusion composition (P=0.005) were significantly associated with the time to recurrence of middle ear effusion. Ears with purulent (mean, 567 days) and glue-like (mean, 588 days) effusions exhibited a shorter time to recurrence than ears with serous (mean, 846 days) or mucoid (mean, 925 days) effusions. The revision VT rates during follow-up were 3.5%, 15.5%, 10.4%, and 38.9% in ears with serous, mucoid, glue-like, and purulent effusions, respectively (P<0.001). The revision surgery rates were higher among patients aged <7 years than among those aged ≥7 years., Conclusion: Silicone tubes (Paparella type I) were less prone to early extrusion than titanium 1.0 mm tubes. VT type, patient age, and effusion composition affected the time to recurrence of effusion.

Folic acid (FA) is essential for human health, particularly for pregnant women and infants. In this work, a glassy carbon electrode (GCE) was modified by a bimetallic layer of Cu/Co nanoparticles (CuNPs/CoNPs) as a synergistic amplification element by simple step-by-step electrodeposition, and was used for sensitive detection of FA. The proposed CuNPs/CoNPs/GCE sensor was characterized by differential pulse voltammetry (DPV), electrochemical impedance spectroscopy (EIS) and field emission scanning electron microscopy (FESEM). Then, under optimal conditions, a linear relationship was obtained in the wide range of 110.00-1750.00 μM for the detection of FA with a limit of detection (LOD) of 34.79 μM (S/N = 3). The sensitivity was calculated as 0.096 μA μM -1 cm -2 . Some interfering compounds including glucose (Glc), biotin, dopamine (DA), and glutamic acid (Glu) showed little effect on the detection of FA by amperometry (i-t). Finally, the average recovery obtained was in a range of 91.77-110.06%, with a relative standard deviation (RSD) less than 8.00% in FA tablets, indicating that the proposed sensor can accurately and effectively detect the FA content in FA tablets., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Excessive intake of melamine (MEL) can be harmful to human health, and it is important to establish a rapid and accurate MEL detection method. As the electrochemical activity of MEL is very low, ferrocenylglutathione (Fc-ECG) was used as an electron transfer mediator to assist with the detection of MEL using screen-printed carbon electrode (SPCE). This modified electrode (MEL/Fc-ECG/SPCE) was prepared by stepwise drop-casting and was fully characterized. Results showed that MEL significantly enhanced signal of Fc-ECG/SPCE sensor due to the three p-π conjugated double bonds that facilitated electron transfer. Under optimal conditions, the sensor exhibits two linearities in the range of 0.20-2.00 μM and 8.00-800 μM, with a sensitivity of 15.03 μA·μM -1 ·cm -2 . The selectivity, stability, and reproducibility were investigated and successfully used to detect MEL in raw milk and confirms safety verification of foods. Moreover, a portable testing platform was designed for MEL detection based on a CH32 chip., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: The patient of hypertension and its complication increase fast in the past years. Obesity is thought to be a risk factor for hypertension, and BMI (body mass index) is widely used to evaluate the obesity and hypertension risk. However, the abdominal obesity and visceral fat accumulation are more obvious in the East Asian population. The aim of this study was to evaluate the predictive value of fatty liver for hypertension in the Chinese population., Method: We compared the predictive value of BMI and fatty liver for the hypertension and its complication in 1386 patients with hypertension in Shanghai China., Results: In the analysis of 1386 patients with hypertension in Shanghai China, we found that the prevalence and risk of hypertension and its complications were higher in the fatty liver group than that in the group of BMI≥24. Furthermore, the areas under the ROC curve of fatty liver for hypertension and its complications were superior to that of BMI., Conclusion: These results suggested that fatty liver is a more sensitive early warning for hypertension and its complication than BMI in Chinese population.

Objectives: To evaluate the efficacy of galvanic vestibular stimulation (GVS) for recovering from the locomotor and spatial memory deficits of a murine bilateral vestibular deafferentation (BVD) model., Methods: Male C57BL/6 mice ( n = 36) were assigned to three groups: bilateral labyrinthectomy with (BVD&#95;GVS group) and without (BVD&#95;non-GVS group) the GVS intervention, and a control group with the sham operation. We used the open field and Y maze, and Morris water maze (MWM) tests to assess locomotor and visuospatial cognitive performance before (baseline) and 3, 7, and 14 days after surgical bilateral labyrinthectomy. For the GVS group, a sinusoidal current at the frequency at 1 Hz and amplitude 0.1 mA was delivered for 30 min daily from the postoperative day (POD) 0 to 4 via electrodes inserted subcutaneously close to both the bony labyrinths., Results: Short-term spatial memory was significantly impaired in bilaterally labyrinthectomized mice (BVD&#95;non-GVS group), as reflected by decreased spontaneous alternation performance in the place recognition test and time spent in the novel arm and increased same arm return in the Y-maze test, compared with the control. Long-term spatial memory was also impaired, as indicated by a longer escape latency in the hidden platform trial and a lower percentage of time spent in the target quadrant in the probe trial of the MWM. GVS application significantly accelerated the recovery of locomotion and short-term and long-term spatial memory deficits in the BVD mice., Conclusions: Our data demonstrate that locomotion, short-term, and long-term (at least 2 weeks) spatial memory were impaired in BVD mice. The early administration of sinusoidal GVS accelerated the recovery of those locomotion and spatial memory deficiencies. GVS could be applied to patients with BVD to improve their locomotion and vestibular cognitive functioning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nguyen, Nam, Han, Le and Oh.)

The nano-scale spherical Na 3 V 2 (PO 4 ) 2 F 3 with a NASICON structure phase was prepared with a spray drying technique, and the bagasse in Guangxi, China was selected as the carbon source to prepare Na 3 V 2 (PO 4 ) 2 F 3 /C. The optimal preparation conditions of the composite determined using thermogravimetry, X-ray diffraction, scanning electron microscopy and electrochemical testing were: a calcination temperature of 650 °C and a 20% carbon source. The Na 3 V 2 (PO 4 ) 2 F 3 /C has obvious redox peaks, determined by cyclic voltammetry (CV), at 3.90 V and 3.75 V, 4.32 V and 4.15 V. These two pairs of redox peaks correspond to the escape/intercalation of the two pairs of Li + /Na + . Notably, compared with pure Na 3 V 2 (PO 4 ) 2 F 3 , the specific discharge capacity of Na 3 V 2 (PO 4 ) 2 F 3 /C-20%, which were used as a cathode material for lithium-sodium hybrid ion batteries, increased from 55 mA h g -1 to 125 mA h g -1 , which was an improvement of twofold.

Gold electrodes (GE) were modified by the deposition of copper nanoparticles (CuNPs) and cobalt nanoparticles (CoNPs), followed by drop-casting of the ferrocene derivative FcCO-Glu-Cys-Gly-OH (Fc-ECG), resulting in two enzyme-free electrochemical sensors Fc-ECG/CuNPs/GE and Fc-ECG/CuNPs/GE. The ferrocene-peptide conjugate acts as an effective redox mediator for glucose oxidation, while metal nanoparticles acted as non-biological sites for glucose oxidation. Field emission scanning electron microscopy (FESEM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were carried out for characterization, while differential pulse voltammetry (DPV) was used for glucose quantification. Under optimized conditions, DPV shows a linear relationship between glucose concentration and the peak current. Both sensors showed a surprisingly high sensitivity of 217.27 and 378.70 μA mM -1 cm -2 , respectively. A comparison to other glucose sensors shows a sensitivity that is 25 times higher. The sensors exhibit good reproducibility, stability, and repeatability. In injection experiments, recovery rates were 87.39-107.65% and 100.00-106.88%, respectively., Competing Interests: Authors declare no competing financial interests., (This journal is © The Royal Society of Chemistry.)

Rare earth elements (REEs) are widely used in the industry, agriculture, biomedicine, aerospace, etc, and have been shown to pose toxic effects on animals, as such, studies focusing on their biomedical properties are gaining wide attention. However, environmental and population health risks of REEs are still not very clear. Also, the REEs damage to the nervous system and related molecular mechanisms needs further research. In this study, the L1 and L4 stages of the model organism Caenorhabditis elegans were used to evaluate the effects and possible neurotoxic mechanism of lanthanum(III) nitrate hexahydrate (La(NO 3 ) 3 ·6H 2 O). For the L1 and L4 stage worms, the 48-h median lethal concentrations (LC 50 s) of La(NO 3 ) 3 ·6H 2 O were 93.163 and 648.0 mg/L respectively. Our results show that La(NO 3 ) 3 ·6H 2 O induces growth inhibition and defects in behavior such as body length, body width, body bending frequency, head thrashing frequency and pharyngeal pumping frequency at the L1 and L4 stages in C. elegans. The L1 stage is more sensitive to the toxicity of lanthanum than the L4 stage worms. Using transgenic strains (BZ555, EG1285 and NL5901), we found that La(NO 3 ) 3 ·6H 2 O caused the loss or break of soma and dendrite neurons in L1 and L4 stages; and α-synuclein aggregation in L1 stage, indicating that Lanthanum can cause toxic damage to dopaminergic and GABAergic neurons. Mechanistically, La(NO 3 ) 3 ·6H 2 O exposure inhibited or activated the neurotransmitter transporters and receptors (glutamate, serotonin and dopamine) in C. elegans, which regulate behavior and movement functions. Furthermore, significant increase in the production of reactive oxygen species (ROS) was found in the L4 stage C. elegans exposed to La(NO 3 ) 3 ·6H 2 O. Altogether, our data show that exposure to lanthanum can cause neuronal toxic damage and behavioral defects in C. elegans, and provide basic information for understanding the neurotoxic effect mechanism and environmental health risks of rare earth elements., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study aimed to investigate the disparity in locomotor and spatial memory deficits caused by left- or right-sided unilateral vestibular deafferentation (UVD) using a mouse model of unilateral labyrinthectomy (UL) and to examine the effects of galvanic vestibular stimulation (GVS) on the deficits over 14 days. Five experimental groups were established: the left-sided and right-sided UL (Lt.-UL and Rt.-UL) groups, left-sided and right-sided UL with bipolar GVS with the cathode on the lesion side (Lt.-GVS and Rt.-GVS) groups, and a control group with sham surgery. We assessed the locomotor and cognitive-behavioral functions using the open field (OF), Y maze, and Morris water maze (MWM) tests before (baseline) and 3, 7, and 14 days after surgical UL in each group. On postoperative day (POD) 3, locomotion and spatial working memory were more impaired in the Lt.-UL group compared with the Rt.-UL group ( p < 0.01, Tamhane test). On POD 7, there was a substantial difference between the groups; the locomotion and spatial navigation of the Lt.-UL group recovered significantly more slowly compared with those of the Rt.-UL group. Although the differences in the short-term spatial cognition and motor coordination were resolved by POD 14, the long-term spatial navigation deficits assessed by the MWM were significantly worse in the Lt.-UL group compared with the Rt.-UL group. GVS intervention accelerated the vestibular compensation in both the Lt.-GVS and Rt.-GVS groups in terms of improvement of locomotion and spatial cognition. The current data imply that right- and left-sided UVD impair spatial cognition and locomotion differently and result in different compensatory patterns. Sequential bipolar GVS when the cathode (stimulating) was assigned to the lesion side accelerated recovery for UVD-induced spatial cognition, which may have implications for managing the patients with spatial cognitive impairment, especially that induced by unilateral peripheral vestibular damage on the dominant side., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nguyen, Nam, Kang, Han, Kim, Dieterich and Oh.)

Quercetin (Qu) is one of the most abundant flavonoids in the human diet. High concentrations of Qu can easily cause adverse effects and induce inflammation, joint pain and stiffness. In this study, Heme was used as a sensitive element and deposited and formed nanorods on a glassy carbon electrode (GCE) for the detection of Qu. The Heme/GCE sensor was characterized using scanning electron microscopy (SEM), cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) techniques. Under optimized conditions, the developed sensor presented a linear concentration ranging from 0.1 to 700 μmol·L -1 according to the CV and DPV methods. The detection limit for the sensor was 0.134 μmol·L -1 and its sensitivity was 0.12 μA·μM -1 ·cm -2 , which were obtained from CV analysis. Through DPV analysis we obtained a detection limit of 0.063 μmol·L -1 and a sensitivity of 0.09 μA·μM -1 ·cm -2 . Finally, this sensor was used to detect the Qu concentration in loquat leaf powder extract, with recovery between 98.55-102.89% and total R.S.D. lower than 3.70%. The constructed electrochemical sensor showed good anti-interference, repeatability and stability, indicating that it is also usable for the rapid detection of Qu in actual samples.

Objectives: To investigate the ameliorating effects of sinusoidal galvanic vestibular stimulation (GVS) on vestibular compensation from unilateral vestibular deafferentation (UVD) using a mouse model of unilateral labyrinthectomy (UL). Methods: Sixteen male C57BL/6 mice were allocated into two groups that comprise UL groups with GVS (GVS group, n = 9) and without GVS intervention (non-GVS group, n = 7). In the experimental groups, we assessed vestibulo-ocular reflex (VOR) recovery before (baseline) and at 3, 7, and 14 days after surgical unilateral labyrinthectomy. In the GVS group, stimulation was applied for 30 min daily from postoperative days (PODs) 0-4 via electrodes inserted subcutaneously next to both bony labyrinths. Results: Locomotion and VOR were significantly impaired in the non-GVS group compared to baseline. The mean VOR gain of the non-GVS group was attenuated to 0.23 at POD 3 and recovered continuously to the value of 0.54 at POD 14, but did not reach the baseline values at any frequency. GVS intervention significantly accelerated recovery of locomotion, as assessed by the amount of circling and total path length in the open field tasks compared to the non-GVS groups on PODs 3 ( p < 0.001 in both amount of circling and total path length) and 7 ( p < 0.01 in amount of circling and p < 0.001 in total path length, Mann-Whitney U -test). GVS also significantly improved VOR gain compared to the non-GVS groups at PODs 3 ( p < 0.001), 7 ( p < 0.001), and 14 ( p < 0.001, independent t -tests) during sinusoidal rotations. In addition, the recovery of the phase responses and asymmetry of the VOR was significantly better in the GVS group than in the non-GVS group until 2 weeks after UVD (phase, p = 0.001; symmetry, p < 0.001 at POD 14). Conclusion: Recoveries for UVD-induced locomotion and VOR deficits were accelerated by an early intervention with GVS, which implies that GVS has the potential to improve vestibular compensation in patients with acute unilateral vestibular failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nam, Nguyen, Kang, Han and Oh.)

Objectives: To investigate the deficits of spatial memory and navigation from unilateral vestibular deafferentation (UVD) and to determine the efficacy of galvanic vestibular stimulation (GVS) for recovery from these deficits using a mouse model of unilateral labyrinthectomy (UL). Methods: Thirty-six male C57BL/6 mice were allocated into three groups that comprise a control group and two experimental groups, UVD with (GVS group) and without GVS intervention (non-GVS group). In the experimental groups, we assessed the locomotor and cognitive behavioral function before (baseline) and 3, 7, and 14 days after surgical UL, using the open field (OF), Y maze, and Morris water maze (MWM) tests. In the GVS group, the stimulations were applied for 30 min daily from postoperative day (POD) 0-4 via the electrodes inserted subcutaneously close to both bony labyrinths. Results: Locomotion and spatial cognition were significantly impaired in the mice with UVD non-GVS group compared to the control group. GVS significantly accelerated recovery of locomotion compared to the control and non-GVS groups on PODs 3 ( p < 0.001) and 7 ( p < 0.05, Kruskal-Wallis and Mann-Whitney U tests) in the OF and Y maze tests. The mice in the GVS group were better in spatial working memory assessed with spontaneous alternation performance and spatial reference memory assessed with place recognition during the Y maze test than those in the non-GVS group on POD 3 ( p < 0.001). In addition, the recovery of long-term spatial navigation deficits during the MWM, as indicated by the escape latency and the probe trial, was significantly better in the GVS group than in the non-GVS group 2 weeks after UVD ( p < 0.01). Conclusions: UVD impairs spatial memory, navigation, and motor coordination. GVS accelerated recoveries in short- and long-term spatial memory and navigation, as well as locomotor function in mice with UVD, and may be applied to the patients with acute unilateral vestibular failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nguyen, Nam, Kang, Han, Kim, Dieterich and Oh.)

A new metal-organic framework (MOF) compound [Mn 2 (2,2'-bca) 2 (H 2 O) 2 ] n (Mn-MOFs) was successfully synthesized by solvothermal method, and Mn-MOFs@Zn material was prepared by loading zinc phosphate onto Mn-MOFs by ball milling, then Mn-MOFs@Zn was added to the water-based acrylic paint to prepare Mn-MOFs@Zn@acrylic coating. The AC impedance test results showed Mn-MOFs@Zn@acrylic coating has higher corrosion inhibition performance and stability to mild steel when compared with blank coating. The impedance modulus of the blank coating in the low frequency region decreased by 90%, and the R ct showed a trend of first increasing and then decreasing over time, the maximum R ct was only 303.8 Ω, which was only Mn-MOFs@Zn@acrylic coating one-seventh of the R ct value. The artificial scratch experiment showed that the Mn-MOFs@Zn@acrylic coating only slightly corrodes at the scratches, because Mn-MOFs@Zn material made the coating a self-repairing function and improved the durable anticorrosion performance of the acrylic coating., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Influenza viruses exacerbate chronic obstructive pulmonary disease (COPD) with considerable morbidity and mortality. Zanamivir and oseltamivir are effective in treating influenza. However, their efficacy in relieving influenza symptoms in COPD patients remains unknown, with the lack of controlled trials in this subject. Therefore, we conducted this randomized controlled trial to investigate the clinical efficacy of both interventions in this population. Patients were allocated to two groups (80 patients each): oseltamivir (OSELTA) and zanamivir (ZANA) groups. Oseltamivir (75 mg) was orally administered twice daily for 5 days, while zanamivir (10 mg) was inhaled twice daily for 5 days. Clinical parameters including body temperature, influenza symptoms (i.e., sore throat, cough, etc.), and serial blood tests were recorded on days 1, 3, and 7. We analyzed primary (changes in body temperature) and secondary outcomes (changes in non-specific symptoms) using the pre-protocol and intention-to-treat analyses. Differences between groups were assessed using t-test. Oseltamivir and zanamivir significantly reduced body temperature on the 3rd day after treatment; however, the number of patients who reported clinical improvement in influenza-like symptoms was significantly higher in the OSELTA group compared to the ZANA group on days 3 (85 vs 68.8%, P=0.015) and 7 (97.5 vs 83.8%, P=0.003). However, no significant changes in hematological (white blood cells and its subtypes) and inflammatory (C-reactive protein) parameters were noted (P>0.05). Our results suggested that oseltamivir and zanamivir are effective in reducing body temperature, while oseltamivir led to better clinical improvement regarding influenza-like symptoms in patients with COPD.

Metastatic castration-resistant prostate cancer (mCRPC) is immunologically "cold" and predominantly resistant to immune checkpoint therapy due to few tumor-infiltrating T cells. Ipilimumab (anti-CTLA-4) or anti-PD-1/PD-L1 monotherapy failed to show a significant benefit. Although the PD-1/PD-L1 pathway is minimally expressed in prostate tumors, we previously demonstrated that PD-1/PD-L1 expression increases as a compensatory inhibitory pathway in parallel with an ipilimumab-induced increase in tumor-infiltrating T cells. Here, we report the largest trial to date in mCRPC with anti-CTLA-4 plus anti-PD-1 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; CheckMate 650, NCT02985957). With median follow-ups of 11.9 and 13.5 months in cohorts 1 (pre-chemotherapy; n = 45) and 2 (post-chemotherapy; n = 45), objective response rate was 25% and 10%, and median overall survival was 19.0 and 15.2 months, respectively. Four patients, two in each cohort, had complete responses. Exploratory studies identify potential biomarkers of response. Grade 3-4 treatment-related adverse events have occurred in ∼42%-53% of patients, with four treatment-related deaths. Therefore, dose/schedule modifications have been implemented., Competing Interests: Declaration of Interests P.S. reports stock options and advisory fees from Oncolytics, Jounce, BioAlta, Forty-Seven, Polaris, Marker Therapeutics, Codiak, ImaginAB, Hummingbird, Dragonfly, Lytix, Lava Therapeutics, Achelois, Infinity, and Glympse, and stock options with BioNTx and Constellation, outside the submitted work. R.P. reports personal fees and non-financial support from Bristol Myers Squibb (BMS) and Genentech/Roche; personal fees from Dendreon, EMD Serono/Pfizer, Genomic Health, AstraZeneca, Sanofi, Merck, Bayer, and Jounce Therapeutics; and institutional grants from Janssen, outside the submitted work. V.N. reports research grants paid to the institution from BMS, during the conduct of the study; research grants paid to the institution from Pfizer and Peloton Therapeutics; research grants paid to the institution and personal fees from Janssen; and personal fees from AstraZeneca, outside the submitted work. A.F. reports personal fees from Astellas, Sanofi, Janssen, AAA, and BMS, outside the submitted work. G.G. reports personal fees from Pfizer, BMS, MSD, AstraZeneca, Astellas, Janssen, Bayer, Sanofi, and Ipsen, outside the submitted work. M.D.G. reports personal fees from BioMotiv, Janssen, Astellas, Pfizer, EMD Serono, Seattle Genetics, Incyte, Dracen, Inovio, Dragonfly, and Aileron; research grants from Dendreon and Novartis; and research grants and personal fees from Merck, Genentech, BMS, and AstraZeneca, outside the submitted work. H.M. reports personal fees and travel fees from BMS and Sanofi, travel fees from Bayer, congress fees from Roche, and personal fees from Ipsen, Janssen, and Astellas, outside the submitted work. A.P. reports funding support for this clinical trial from BMS during the conduct of the study; grants from Prostate Cancer Foundation, Phi Beta Psi Charity Trust Research Organization, National Cancer Institute, BMS, and Progenics; grants and personal fees from Clovis; and personal fees from Exelixis, PRIME, Janssen, Jounce Therapeutics, Guidepoint, Merck, and Gerson Lehrman Group, outside of the submitted work. S.K.S reports personal fees from Exelixis, Dava Oncology, Cancer Now, Polaris, and MEDACorp; grants and non-financial support from Parker Institute for Cancer Immunotherapy; grants, personal fees, and non-financial support from Janssen Oncology, AstraZeneca, and BMS; personal fees and non-financial support from Dendreon, Amgen, Bayer, and Society for Immunotherapy of Cancer; and personal fees and ownership interests from Apricity Health, outside the submitted work. M.C. is an employee of and shareholder in BMS. B.S. is an employee of and shareholder in BMS. G.C.H. is an employee of BMS. A.S. is a former employee of and shareholder in BMS. Y.H. is an employee of and shareholder in BMS. K.F. reports personal fees from Amgen, Astellas, AstraZeneca, AAA, Bayer, Clovis, Curevac, ESSA, Genentech, Janssen, MSD, Orion, and Sanofi, outside the submitted work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Congenital aural atresia is an ear malformation evident at birth, involving various degrees of failed external ear canal development. A true external ear canal is desirable, as devices that replace the canal are inconvenient and expensive. Therefore, an optimal surgical technique is required. Here, we review useful preoperative and operative techniques. Surgical correction is often not the preferred treatment; the hearing outcome is no better than the outcomes afforded by bone-conduction devices, and surgery may be associated with recurrence or complications such as meatal stenosis. Preoperative evaluation and appropriate management are important. Several means of preventing meatal stenosis are discussed in this review.

Purpose: We report efficacy and safety with extended follow-up, and exploratory biomarker analyses from the phase II CheckMate 275 trial to identify biomarkers of response to nivolumab in platinum-resistant metastatic or unresectable urothelial carcinoma (mUC)., Patients and Methods: Patients received nivolumab 3 mg/kg once every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was objective response rate (ORR) per blinded independent review committee (BIRC; using RECIST v1.1) in all treated patients and by tumor PD-L1 expression. Key secondary endpoints were progression-free survival (PFS) per BIRC using RECIST v1.1 and overall survival (OS) in all patients and by PD-L1 expression. Exploratory endpoints included safety and biomarker analyses of tumor mutational burden (TMB), PD-L1, and previously identified mutational signatures., Results: Of 270 treated patients, 139 had evaluable TMB. With 33.7 months' minimum follow-up, ORR per BIRC, median PFS, and median OS [95% confidence interval (CI)] in all treated patients were 20.7% (16.1-26.1), 1.9 months (1.9-2.3), and 8.6 months (6.1-11.3), respectively. No new safety signals were identified. Higher TMB was associated ( P < 0.05) with improved ORR [OR (95% CI): 2.13 (1.26-3.60)], PFS [HR: 0.75 (0.61-0.92)], and OS [HR: 0.73 (0.58-0.91)]. TMB combined with PD-L1 better predicted ORR, PFS, and OS than PD-L1 alone. Higher mutational signature 2 score was associated with better OS but did not improve the predictive value of TMB., Conclusions: These results support the durable antitumor activity of nivolumab and suggest that TMB may enrich for better response in mUC. Future studies of TMB/PD-L1 as biomarkers for response to nivolumab in randomized trials are warranted. See related commentary by Swami et al., p. 5059 ., (©2020 American Association for Cancer Research.)

Several simple sensors were fabricated through a one-step method. By depositing electro-active compounds, such as β-cyclodextrins (β-CD), heme, dopamine (DA), or Fc-ECG, onto a screen-printed electrode (SPE), the successful simultaneous detection of nitrite (NO 2 - ) and thiosulfate (S 2 O 3 2- ) ions was observed. Under optimal operating conditions, the notable electrocatalytic abilities of a Heme/SPE sensor were detected for the oxidation of NO 2 - and S 2 O 3 2- , with remarkable peak potential differences, after characterization via SEM, CV, and DPV. Linear relationships were obtained in the ranges of 5.0-200.0 μmol L -1 and 1.0-100.0 μmol L -1 for the current response versus concentration of NO 2 - and S 2 O 3 2- , respectively. The limits of detection were determined to be 1.67 and 0.33 μmol L -1 while the sensitivities of detection were noted to be 0.43 and 1.43 μA μM -1 cm -2 , respectively. During the detection of NO 2 - and S 2 O 3 2- , no interfering common ions were observed. Furthermore, average recoveries from 96.0 to 104.3% and a total R.S.D. of less than 3.1% were found for the detection of NO 2 - and S 2 O 3 2- in pickled juice and tap water using the simple sensor. These results showed that rapid and precise measurements for actual application in NO 2 - and S 2 O 3 2- detection could be conducted in food samples, indicating a potential use in food safety., Competing Interests: The authors declare no competing financial interests., (This journal is © The Royal Society of Chemistry.)

Two unreported metal-organic frameworks [Cu(6-Me-2,3-pydc)(1,10-phen)·7H 2 O] n (namely Cu-MOF) and [Mn 2 (2,2'-bca) 2 (H 2 O) 2 ] n (namely Mn-MOF) were synthesized by a solvothermal method and their structures were characterized and confirmed by elemental analysis, X-ray single crystal diffraction, Fourier infrared spectroscopy and thermogravimetric analysis. Cu-MOF/graphene (Cu-MOF/GR), Cu-MOF/graphene oxide (Cu-MOF/GO), Mn-MOF/graphene (Mn-MOF/GR) and Mn-MOF/graphene oxide (Mn-MOF/GO) composite materials were successfully synthesized by a solvothermal method and characterized and analyzed by PXRD, SEM and TEM. In order to study the corrosion inhibition properties of the Cu-MOF/GR, Cu-MOF/GO, Mn-MOF/GR and Mn-MOF/GO composite materials on carbon steel, they were mixed with waterborne acrylic varnish to prepare a series of composite coatings to explore in 3.5 wt% NaCl solution by electrochemical measurements and results showed that the total polarization resistance of the 3% Cu-MOF/GO and 3% Mn-MOF/GO composite coatings on the carbon steel surface were relatively large, and were 55 097 and 55 729 Ω cm 2 , respectively, which could effectively protect the carbon steel from corrosion. After immersion for 30 days, the 3% Mn-MOF/GO composite still maintained high corrosion resistance, the | Z | values were still as high as 23 804 Ω cm 2 . Therefore, MOFs compounded with GO can produce a synergistic corrosion inhibition effect and improve the corrosion resistance of the coating; this conclusion is well confirmed by the adhesion capability test., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objectives: We hypothesized that immune response may contribute to progression of coronavirus disease-19 (COVID-19) at the second week of illness. Therefore, we compared cell-mediated immune (CMI) responses between severe and mild COVID-19 cases., Methods: We examined peripheral blood mononuclear cells of laboratory-confirmed COVID-19 patients from their first and third weeks of illness. Severe pneumonia was defined as an oxygen saturation ≤93% at room air. Expressions of molecules related to T-cell activation and functions were analyzed by flow cytometry., Results: The population dynamics of T cells at the first week were not different between the two groups. However, total numbers of CD4 + and CD8 + T cells tended to be lower in the severe group at the third week of illness. Expressions of Ki-67, PD-1, perforin, and granzyme B in CD4 + or CD8 + T cells were significantly higher in the severe group than in the mild group at the third week. In contrast to the mild group, the levels of their expression did not decrease in the severe group., Conclusions: Severe COVID-19 had a higher degree of proliferation, activation, and cytotoxicity of T-cells at the late phase of illness without cytotoxic T-cell contraction, which might contribute to the development of severe COVID-19., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In this work, two new bis-Schiff bases, namely 2-bromoisophthalaldehyde-2-aminofluorene (M1) and glutaraldehyde 2-aminofluorene (M2), were synthesized, and their structures were characterized and confirmed by infrared spectroscopy, Fourier transform mass spectrometry and UV-visible spectroscopy. Their corrosion inhibition performance on carbon steel in simulated circulating cooling water was investigated by weight loss measurements and electrochemical measurements. The potentiodynamic polarization curves confirmed that two bis-Schiff bases are anode-type inhibitors; electrochemical impedance spectroscopy tests showed that M1 and M2 possess the best inhibition efficiencies of 96.25% and 99.15% at the optimal concentration of 2.50 mmol L -1 , respectively. The weight loss results showed that M1 and M2 exhibit maximum η w values of 92.62% and 96.31%, respectively. Scanning electron microscopy showed that the inhibitors inhibited carbon steel corrosion. The adsorption isotherm measurements indicated that the two inhibitors exhibited physicochemisorption mechanisms and followed Langmuir adsorption isotherms. The relationships between the molecular structure and inhibition behavior of the inhibitors were explored by density functional theory, frontier molecular orbital studies, and Fukui index analysis, which affirmed that M2 possesses higher corrosion inhibition efficiency than M1., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

A 39-year-old man visited the department of otolaryngology due to an ongoing hearing disturbance that had lasted for 1 year. Temporal bone computed tomography revealed soft tissue density nearly obliterating the left external auditory canal (EAC). The mass was composed of sheets of round tumor cells containing moderate amounts of fine granular cytoplasm and salt and pepper chromatin. Neither mitosis nor necrosis was found. The Ki-67 proliferation index was less than 2%. Cells were positive for CD56 and synaptophysin but negative for chromogranin, cytokeratin (CK) 20, and CK7. Based on these findings, the tumor was diagnosed as a carcinoid tumor, well differentiated neuroendocrine carcinoma, grade 1 (G1) according to current World Health Organization (WHO) classification of head and neck tumors; and a neuroendocrine tumor, G1 according to neuroendocrine neoplasm (NEN)-2018 WHO standard classification. He remained free of local recurrence and metastasis after 20 months of follow up. To date, only six cases of primary NENs in the EAC have been reported. Metastatic tumor should be included in the differential diagnoses. Because of its rarity, the prognosis and treatment have not yet been clarified.

A novel 3D paper-based microfluidic screen-printed electrode (SPE) composed of two layers was constructed by photolithography and screen-printing technology. Aldehyde functionalized hydrophilic zone of the counter and reference electrodes layer was prepared for glucose oxidase immobilization. Highly conductive prussian blue deposited reduced graphene oxide-tetraethylene pentamine (rGO-TEPA/PB) modified paper working electrode layer can be used as an electrochemical sensitive membrane for quantitative detection of hydrogen peroxide (H 2 O 2 ), which was the enzyme-catalyzed reaction product. Therefore, this 3D paper-based microfluidic electrochemical biosensor can be used for quantitative detection of glucose. Under optimum conditions, the proposed biosensor can be used for quantitative determination of glucose over a wide linear range of 0.1 mM-25 mM with detection limit of 25 μM. Finally, the 3D paper-based microfluidic electrochemical biosensor was applied to determine glucose in human sweat and blood, and the obtained results were in good consistency with values measured by Roche's blood glucose meter. In addition, the proposed 3D paper-based electrochemical device showed good repeatability, stability, and anti-interference, which would be of great potential to monitor glucose in complex biological fluids., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Several simple electrochemical sensors were designed for three analytes, uric acid (UA), dopamine (DA) and ascorbic acid (AA) detection via electrolytic deposition of three functional materials heme, Fc(Cys)₂ and Fc-ECG onto glassy carbon electrodes (GCEs) without other medium. Characterization of the modified GCEs was conducted using SEM, TEM and DPV methods. Results showed that the heme/GCE demonstrated notable electro-catalytic capabilities, towards DA, AA, and UA oxidation in a solution of phosphate buffer. The current signals of DPV technique for three analytes shown up three defined oxidated peaks, the peak potential differences was 192 mV for AA and DA, and 142 mV for DA and UA. Under optimal conditions, it can be obtained linear responses for AA, DA and UA in the following concentration ranges: 10 to 50, 5 to 20, and 2.5 to 20 μ mol·L -1 , and the limits of detection was calculated as 0.76, 0.50 and 0.63 μ mol·L -1 , respectively. The results demonstrated that the heme directly modified GCE was a well-suited electrochemical sensor for determining UA, DA and AA in actual samples.

Simple and facile electrochemical sensors for nitrite detection were fabricated by directly depositing ferrocenoyl cysteine conjugates Fc[CO-Cys(Trt)-OMe]₂ [Fc(Cys)₂] or Fc[CO-Glu-Cys-Gly-OH] [Fc-ECG] on screen-printed electrodes (SPEs). The modified carbon electrodes were characterized by scanning electron microscopy (SEM), cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Results indicated that Fc-ECG/SPE sensor showed enhanced current response and a lower overpotential than Fc(Cys)₂/SPE sensor for nitrite detection. Optimal operating conditions were estimated for nitrite detection by DPV. The concentration of nitrite showed a good linear relationship with the current response in the range of 1.0⁻50 μmol·L -1 and with 0.3 μmol·L -1 as the concentration for limit of detection. There were no interferences from most common ions. The development of this electrochemical sensor was used for nitrite detection in pickled juice with a R.S.D. lower than 2.1% and average recovery lower than 101.5%, which indicated that disposable electrochemical sensor system can be applied for rapid and precise nitrite detection in foods.

Probing the electrical response of the human body is minimally invasive and a promising area of investigation for future health care. The electrical responses of individuals may vary depending on daily physiological rhythms or environmental changes, which may hamper their prediction for pathological status. In this study, we observed circadian expressions via both alternating current (AC) and direct current (DC) electrical responses of the human body using bioelectrical impedance analysis (BIA) and electrodermal activity (EDA). In total, 14 healthy adults (9 males and 5 females) participated and were hospitalized for 2 nights with controlled caloric intake, sleep hours and residential conditions. The EDA data showed a significant circadian rhythm, but the BIA data did not show significant modulations during the measurement period. No difference was found between circadian changes in male and female participants. The acrophase of the EDA voltage response showed similar behavior with variations in the heart rate variability, with a resistance minimum occurring at approximately 4 pm, implying that the behavior of the EDA is probably affected by the sympathetic nerve response. Moreover, the resistance of the EDA varied by up to 15% from its mean value, which suggests that circadian variations cannot be neglected for the correct diagnosis of pathological conditions. In contrast, the BIA method did not show this circadian variation but showed independent results over the measurement period. This difference in performance implies that the DC and AC responses of the human body contain different electrophysiological information.

Objectives: The aim of this multicenter registry study was to investigate the effectiveness of ventilation tube insertion and the microbiology of otitis media with effusion (OME) in children. This part I study was conducted to evaluate the microbiological profile of children with OME who needed ventilation tube insertion., Methods: Patients <15 years old who were diagnosed as having OME and received ventilation tube insertion were prospectively enrolled in 16 tertiary hospitals from June 2014 to December 2016. After excluding patients with missing data, the data of 397 patients were analyzed among a total of 433 enrolled patients. The clinical symptoms, findings of the tympanic membrane, hearing level, and microbiological findings were collected., Results: In 103 patients (25.9%), antibiotics were used within 3 weeks before surgery. Ventilation tube insertion was performed in a total of 710 ears (626 in both ears in 313 patients, 55 in the left ear only, and 29 in the right ear only). Culture of middle ear effusion was done in at least one ear in 221 patients (55.7%), and in a total of 346 ears. Only 46 ears (13.3%) showed positive results in middle ear effusion culture. Haemophilus influenzae (17.3%, followed by coagulase-negative Staphylococcus and Staphylococcus auricularis ) was the most common bacteria detected., Conclusion: H. influenzae was the most commonly found bacteria in middle ear effusion. Relatively low rates of culture positivity were noted in middle ear effusion of patients with OME in Korea.

Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway. We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer, such as the ubiquitin ligase CUL3 and the transcription factor SPEN. Finally, comparing primary and metastatic prostate cancer identifies a set of genomic markers that may inform risk stratification.

Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAF V600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo In vitro , the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome. Significance: We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in BRAF V600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 417-27. ©2018 AACR. See related commentary by Janku, p. 389 See related article by Corcoran et al., p. 428 This article is highlighted in the In This Issue feature, p. 371 ., (©2018 American Association for Cancer Research.)

Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. Of the 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC-susceptibility genes, and another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations in ATM and PALB2 were enriched in both the discovery (OR = 2.81 and p = 0.035 for ATM and OR = 4.91 and p = 0.024 for PALB2) and validation (OR = 2.97 and adjusted p = 0.0013 for ATM and OR = 3.42 and adjusted p = 0.034 for PALB2) sets. Biallelic loss of ATM was evident in all individuals with matched tumor profiling. CRC individuals also had higher rates of actionable mutations in the HR pathway, which can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence for ATM and PALB2 as CRC-risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as poly-ADP ribose polymerase inhibitor (PARPi)., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Pulmonary fibrosis (PF) is a chronic, fibrosing interstitial pneumonia and devastating disease. Here we investigated the potential roles of Kruppel-like factor 2 (KLF2) on pulmonary fibrosis and inflammation response. A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM). The mRNA and protein levels of KLF2 were assayed by RT-PCR and Western blotting respectively. The extent of lung fibrosis was determined using hematoxylin and eosin (HE) staining and Masson's trichrome staining, and the hydroxyproline content was quantified. RT-PCR was used to evaluate the mRNA expression of collagen type 1a1 (col1a1), col3a1, α-SMA, TNF-α, IL-1β and IL-6. The concentrations of TNF-α, IL-1β, and IL-6 in bronchoalveolar lavage fluid (BALF) and lung tissue were examined by ELISA. Also, the effects of KLF2 on activator protein-1 (AP-1) were evaluated by measuring the c-Jun and c-Fos protein levels. We found that KLF2 was remarkably downregulated in BLM-treated rats, both in mRNA and protein levels. Additionally, overexpression of KLF2 attenuated the destruction of the alveolar space and pulmonary interstitial collagen hyperplasia, and deposition reduced the expression of col1a1, col3a1, and α-SMA, and blocked the production of TNF-α, IL-1β, and IL-6 in BALF and lung tissue in vivo. Moreover, adenoviral transduction of KLF2 inhibited TGF-β1-induced expression of col1a1, col3a1, and α-SMA in vitro. Mechanically, BLM up-regulated c-Jun and c-Fos expression, which was impeded by KLF2 overexpression. Taken together, our data indicate that KLF2 attenuates pulmonary fibrosis and inflammation, possibly through the regulation of AP-1., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Patients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy., Patients and Methods: We analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgen-deprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor., Results: We observed that abiraterone-resistant tumors harbored alterations in AR and MYC , whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A ( CDKN2A ) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade-palbociclib and ribociclib., Conclusion: CDK4/6 -mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamide-resistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. G. Celine HanStock and Other Ownership Interests: Amgen, Amarin Corporation, OrganovoJustin HwangNo relationship to discloseStephanie A.M. WankowiczNo relationship to discloseZhenwei ZhangNo relationship to discloseDavid LiuNo relationship to discloseCarrie CibulskisNo relationship to discloseGlenn C. GaviolaNo relationship to discloseVarand GhazikhanianNo relationship to discloseRana R. McKayResearch Funding: Pfizer (Inst), Bayer (Inst)Glenn J. BubleyNo relationship to discloseScott L. CarterNo relationship to discloseSteven P. BalkHonoraria: Janssen Pharmaceuticals Consulting or Advisory Role: Sanofi Patents, Royalties, Other Intellectual Property: License to NKT Therapeutics for an antibody Expert Testimony: Astellas Medivation Travel, Accommodations, Expenses: Janssen PharmaceuticalsWilliam C. HahnStock and Other Ownership Interests: Blueprint Medicines Consulting or Advisory Role: Novartis, Thermo Fisher Scientific Life Sciences, AJU IB, MPM Capital, KSQ Therapeutics Research Funding: NovartisMary-Ellen TaplinHonoraria: Medivation, Janssen-Ortho, Clovis Oncology, Bayer Consulting or Advisory Role: Medivation, Janssen-Ortho, Sanofi, Bayer, Guidepoint Global, Best Doctors, UpToDate, Clovis Oncology, Research to Practice, DAVAOncology, Myovant Research Funding: Janssen-Ortho (Inst), Medivation (Inst), Genentech (Inst), Bayer (Inst), Tokai Pharmaceuticals (Inst) Travel, Accommodations, Expenses: Medivation, Janssen Oncology, Tokai PharmaceuticalsEliezer M. Van AllenStock and Other Ownership Interests: Syapse, Tango Therapeutics, Genome Medical Consulting or Advisory Role: Syapse, Roche, Third Rock Ventures, Takeda Pharmaceuticals, Novartis, Genome Medical, InVitae Speakers' Bureau: Illumina Research Funding: Bristol-Myers Squibb, Novartis, (© 2017 by American Society of Clinical Oncology.)